Sunscreen to Protect the Marrow
Authors: Melania Tesio
Journal: HemaSphere (2023)

During clonal hematopoiesis, the emergency of preleukemic mutations in hematopoietic stem cells affects not only their clonal outgrowth but also the function of differentiated immune cells, which inherit the genetic lesions from their mutant precursors. When migrating from the bone marrow to peripheral tissues, immune cells bearing preleukemic alterations, such as TET2, trigger exacerbated inflammatory responses, which increase the risks for cardiovascular and pulmonary diseases and other pathological conditions.1 Although extensive investigations have linked mutant immune cells clones to disease development in distinct nonhematopoietic organs, it remains unclear how the exposure to tissue-specific environmental factors in these organs affects the clones of immune progenitor cells bearing preleukemic mutations and their leukemic evolution. In a recent Nature issue, Gabriel Griffin and colleagues provided very interesting data on this topic.2 The authors focused on blastic plasmacytoid cell neoplasm (BPDCN), an unusual leukemia presenting with malignant cells in the skin. Although the bone marrow is not necessarily involved at diagnosis, it is often disseminated during disease progression.3 Albeit rare, this malignancy offers a paradigmatic model to study leukemia ontogeny across distinct anatomical sites and thus to explore the effect of tissue-specific environmental factors on the evolution of premalignant hematopoietic clones. Targeted sequencing of 16 bone marrow samples from patients with both skin and bone marrow involvement and cases with only skin lesions revealed pathogenic mutations in 94% of the cohort. Affecting genes commonly altered in clonal hematopoiesis, these mutations showed a high variant allele frequency in the vast majority of individuals without bone marrow infiltration, indicating their presence in preleukemic bone marrow clones. This led the authors to combine whole-genome, whole-exome, and targeted sequencing of premalignant bone marrow clones and skin tumors at diagnosis to reconstruct the tumors phylogenies. Interestingly, while most bone marrow mutations were found in matched skin tumors, the alterations found in skin tumors were unique to the skin. These evidences, indicating that BPDCN originates from clonally expanded progenitor cells in the bone marrow, next prompted the authors to analyze clonal architectures and to identify founder clones (ie, those containing recurrent alterations in TET2, ASXL1, and splicing-factors) and progression mutations (ie, activating RAS mutations and CDKN2A loss). When these data were integrated with single cell RNA-sequencing analysis, this revealed that founder and progression mutations were contained in a population of cells classified as plasmacytoid dendritic cells (pDCs) and overrepresented in the cellular hierarchies of patients with bone marrow involvement. These cells, moreover, showed a high enrichment for a BPDCN signature. In contrast, in patients without marrow involvement, whereby cellular hierarchies were similar to healthy controls, pDC showed low BPDCN signatures score and they exclusively contained founder mutations. These data, consistent with a scenario whereby bone marrow preleukemic pDC cells mutationally evolve to malignant BPDCN, raise 2 types of questions. First, as BPDCN founder mutations are common to clonal hematopoiesis lesions, do premalignant pDCs arise from clonal mutant multipoint progenitor cells or rather from mutational events occurring in lineage committed pDC progenitors? As evidenced by the analysis of founder mutations across the hematopoietic hierarchies, the first scenario is the most likely to occur because founder mutations were found across progenitors, erythroid/myeloid, and lymphocyte populations. Second, in which organ does the transformation occur? Are premalignant pDCs transformed in the bone marrow and next migrating to the skin? Or do the premalignant pDCs spreading to the skin undergo transformation in this organ before homing back to bone marrow? To discriminate between these 2 possibilities, the authors analyzed mutational signatures across skin and bone marrow samples, showing that skin tumors are enriched for a UV-associated signature. Interestingly, moreover, the authors managed to identify circa 4000 bone marrow cells with UV-mutations and they showed that they could be transcriptionally classified as BPDCN malignant cells; hence, suggesting a scenario whereby malignant cells in the bone marrow have previously transited to the skin where they acquired UV-mutations. This was further corroborated by the overlay of UV mutations onto a patient’s detailed tumor phylogeny, which showed that UV-induced lesions occur before the acquisition of progression mutations such as CDKN2A. Remarkably, however, these UV-induced mutations are likely not to induce direct oncogenic events. As evidenced in the murine setting, these mutations are instead rather acting as a selective pressure for premalignant pDCs, which in the absence of TET2 escape cell death. Hence, in the model that emerges from these data, clonal premalignant pDCs arising from clonal progenitors in the bone marrow are transformed in the skin under the selective pressure of UV exposure and next home back to the bone marrow where they promote the leukemic dissemination (Figure 1).Figure 1.: Model of BPDCN ontogeny proposed by Griffin et al. BPDCN = blastic plasmacytoid cell neoplasm; HSCs = hematopoietic stem cells; MPPs = multipoint progenitors; pDCs = plasmacytoid dendritic cells.Although clinical evidence previously suggested BPDCN potentially originates both in the bone marrow and the skin, the model by Griffin et al predicts a step-wise evolution model across distinct anatomical sites, and reconciles these observations. This model holds promise for potentially improving the early diagnosis and progression of a disease that albeit rare remains clinically challenging. In addition, by clarifying BPDCN ontogeny, the work by Griffin et al elegantly demonstrates the role of tissue-specific environmental factors in promoting leukemia evolution from clonal progenitors. AUTHOR CONTRIBUTIONS MT conceived and wrote the article. DISCLOSURES The author has no conflicts of interest to disclose. SOURCES OF FUNDING MT declares a Grant from Ligue contre le Cancer.